1. Field of the Invention
The present invention relates to the field of pharmaceutical formulations of a non-nucleoside reverse transcriptase inhibitor. More specifically, the present invention relates to novel formulations of etravirine and uses thereof.
2. Description of the Related Art
Non-nucleoside reverse transcriptase inhibitors are a key component of highly active antiretroviral therapy (HAART) because of their ability to target an allosteric binding pocket on the reverse transcriptase enzyme giving rise to a broad spectrum of activity against Human Immunodeficiency Virus (HIV) reverse transcriptase mutations. HAART has been the standard of care for HIV infection since 1996 and has resulted in substantial increases in survival. Diarylpyrimidine compounds represent second-generation non-nucleoside reverse transcriptase inhibitors and are useful for treatment of HIV infected patients with non-nucleoside reverse transcriptase inhibitor-resistant viruses.
Etravirine (I), formerly TMC 125 and chemically known as 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl benzonitrile, is an non-nucleoside reverse transcriptase inhibitor approved in 2008 for use in combination with other antiretroviral agents in treatment-experienced adult patients with multidrug-resistant HIV infections. Etravirine is marketed worldwide as an oral tablet and was first disclosed by De Corte et al. in U.S. Pat. No. 7,037,917.
Etravirine is the first drug in the second generation of non-nucleoside reverse transcriptase inhibitors and has been recently marketed for the treatment of HIV infection (1). Etravirine is more potent than other first generation non-nucleoside reverse transcriptase inhibitors due to its activity against non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 (2). The recommended dose of this drug is 200 mg (or two 100 mg tablets) taken twice daily following a meal (3).
Etravirine is highly bound to plasma proteins and is primarily metabolized by cytochrome P450 CYP 3A4, 2C9, and 2C19 enzymes. According to the Biopharmaceutics Classification System, etravirine is a class IV compound (low water solubility and permeability). This highly lipophilic drug contains an octanol:water partition coefficient (logP) greater than 5, along with an ionization constant (pka) of 3.75 (4). Despite the use of etravirine in the clinical management of HIV infected patients, limited pharmacokinetic information is available regarding the absorption, distribution, metabolism, and excretion following oral administration (5).
There is a need in the art for an oral liquid dosage formulation, especially for those AIDS patients who are often unable to swallow a pill. There is, furthermore, a need to develop a more bioavailable formulation of etravirine to facilitate better clinical outcomes. The prior art is deficient in improved etravirine oral formulations and uses thereof. The present invention fulfils this longstanding need in the art.